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Claudia SEW Schuurhuizen,1,2 Henk MW Verheul,1 Annemarie MJ Braamse,3 Laurien M Buffart,1–4 Haiko J Bloemendal,5 Joost Dekker,2,6,* Inge RHM Konings1,* 1Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands; 2Department of Psychiatry, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands; 3Department of Medical Psychology, Academic Medical Center Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands; 4Department of Epidemiology and Biostatistics, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands; 5Department of Medical Oncology, Meander Medical Center, Amersfoort, The Netherlands; 6Department of Rehabilitation Medicine, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands *These authors contributed equally to this work Background: Studies evaluating new systemic agents tend to report severe toxicities only, while the cumulative effect of multiple lower grade adverse events (AEs) may have an additional negative impact on patient quality of life (QOL). In the current observational cohort study, we evaluated whether, in patients with metastatic colorectal cancer receiving first-line chemotherapy, cumulative toxicity comprising all grades of AEs is more predictive for QOL than cumulative toxicity due to only high-grade AEs.Methods: One hundred and five patients starting treatment completed the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) questionnaire at baseline and 10 weeks. AEs, clinical outcomes, and demographics were retrieved from patient records. Cumulative toxicity scores were calculated in three ways: total number of high-grade AEs, total number of all-grade AEs, and total number of AEs multiplied by their grade (the severity score). Relations between cumulative toxicity scores and QOL were studied using multivariable linear regression analyses.Results: The mean age of patients was 65 years, 68% were male, and 84% received oxaliplatin-based chemotherapy. A higher total number of AEs of all grades (B=−2.4, 95% CI=–3.9; –0.9) and the severity score (B=–1.4, 95% CI=–2.3; –0.5) were predictive for clinically relevant changes in physical QOL, whereas the total high-grade AEs was not. None of the cumulative toxicity scores were predictive for global QOL.Conclusion: Cumulative toxicity scores comprising all grades of AEs provide a better measure of treatment burden than a toxicity score comprising high-grade AEs only. Physical QOL seems to be more affected by AEs than global QOL. Our results emphasize that future clinical trials should present cumulative toxicity scores comprising all AE grades as well as physical QOL instead of global QOL. Keywords: cumulative toxicity, treatment-related toxicity, adverse events, quality of life, metastatic colorectal cancer

Purpose: To better understand the mechanisms underlying (in)sensitivity of tumors to anticancer drugs, assessing intra-tumor drug pharmacokinetics (PKs) could be important. We explored the feasibility of microdialysis in tumor tissue for multiple days in a clinical setting, using carboplatin as model drug.Methods: Plasma and microdialysate samples from tumor and adipose normal tissues were collected up to 47 h after dosing in eight carboplatin-treated patients with an accessible (sub)cutaneous tumor.Results: Pharmacokinetics were evaluable in tumor tissue in 6/8 patients and in adipose normal tissue in 3/8 patients. Concentration-time curves of unbound platinum in both the tissues followed the pattern of the curves in plasma, with exposure ratios of tissue versus plasma ranging from 0.64 to 1.46.Conclusions: Microdialysis can be successfully employed in ambulant patients for multiple days, which enables one to study tissue PK of anticancer drugs in normal and malignant tissues in more detail. [ABSTRACT FROM AUTHOR]

Purpose: After completion of curative cancer treatment patients enter the re-entry phase, which is characterized by the task to pick up life again. While having to resume their former roles, patients experience the loss of normality and face existential concerns. A sense of meaning and purpose may help in dealing with changes in life and existential concerns. The aim of this study is to gain insight in the meaning-making process of patients treated for breast cancer or melanoma in the re-entry phase in order to develop an intervention to support picking up life after a long treatment process including systemic treatment., Methods: We conducted six focus groups with 16 patients (11 breast cancer and five melanoma) to explore their experiences, challenges, and sources of meaning during the re-entry phase. The re-entry phase was defined as the point from completion of surgical and systemic treatment (except for hormonal therapy) up to 18 months in remission. A thematic content analysis was performed by two researchers., Results: We identified four themes pertaining to patients' use of sources of meaning in the meaning-making process: (1) use of existing, helpful sources; (2) distress due to impacted sources; (3) search for new sources; and (4) use of adapted or new sources. When patients drew upon existing sources of meaning that had been impacted by cancer and the aftermath of treatment, they experienced distress. This could instigate a search resulting in adapted, strengthened, or new sources of meaning., Conclusions: Meaning-making in the re-entry phase is a versatile process involving the use of existing sources of meaning, and a search for, or use of new, strengthened, or adapted sources of meaning. An intervention increasing patients' awareness of their sources of meaning might strengthen the meaning-making process of patients treated for breast cancer or melanoma.

Purpose: To assess information and communication priorities of patients and healthcare professionals in Shared Decision Making about adjuvant systemic treatment of primary breast cancer and identify key decision-relevant information accordingly., Methods: Patients (N = 122) and professionals working with breast cancer patients (N = 118), of whom 38 were nurse practitioners and 32 nurses, were recruited using convenience sampling, and surveyed about information/communication aspects key to decision-making, using ranking assignments. We further posed a simple open question, questions about receiving population-based statistics versus personalized statistics concerning treatment outcomes, and their attitude and experience concerning Shared Decision Making. Data were analyzed using descriptive analysis and a qualitative analysis., Results: Both patients and professionals prioritized information about treatment outcomes (i.e., survival, recurrence) as key decision-relevant information for patients. Patients prioritized information about relatively severe treatment side-effects and late effects (e.g., blood clot, stroke), whilst professionals prioritized information about effects that occur relatively often (e.g., hair loss, fatigue). Patients specifically wanted to know if the benefit of treatment is worth the negative impact. Both groups prioritized personalized statistics over population-based statistics., Conclusions: Some differences between patients and professionals were found in information and communication priorities, specifically related to the different side-effects. It seems worthwhile to precisely address these side-effects in Shared Decision Making concerning adjuvant systemic treatment. Furthermore, it seems important to deliberate together on the question if expected benefit of treatment is worth the potential negative impact for the individual patient., Competing Interests: Declaration of competing interest Domino Determann was working at ‘PATIENT+’ at the time of the study. PATIENT+ is part of the larger consortium; it is a company that provides the patient decision support tool for breast cancer adjuvant therapy that was studied (https://patientplus.info/). The other authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported., Materials and Methods: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models., Results: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status., Conclusions: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials., Competing Interests: Disclosure PJvD has advisory relationships with Paige, Pantarei and Samantree, paid to the institution, and research grants paid to the institute from Pfizer. NS received institutional research funding from Pfizer. ZV has a consulting role for Roche. CHMvD received institutional research funding from AstraZeneca/Daiichi Sankyo. SMW has a consulting role for Roche, and received institutional research funding from Roche, Pfizer, Bayer, MSD, AstraZeneca/Merck and Amgen. SMW has a consulting role for IDDI, Sensorion, Biophytis, Servier, Yuhan, Amaris Consulting and Roche. JW received institutional research funding from Cancer Research UK and KWF Dutch Cancer Society. AR has a consulting role for MSD Oncology, Amgen, Roche, AstraZeneca/Daiichi Sankyo and Bristol Myers Squibb/Pfizer. SCL reports grants from ZonMw and A Sister’s Hope during the conduct of the study; has been an advisory board member for AstraZeneca, Cergentis, IBM, Novartis, Pfizer, Sanofi and Roche; and received institutional research grants from Agendia, AstraZeneca, Eurocept-pharmaceuticals and Merck and Pfizer. In addition, SCL received institutional research grants and institutional non-financial support from Agendia, Genentech, Novartis, Roche, Tesaro and Immunomedics and other institutional support from AstraZeneca, Pfizer, Cergentis, Daiichi Sankyo, IBM and Bayer outside the submitted work. MK is an advisory board member and/or received speakers’ fee for/from Alderaan, Bristol Myers Squibb (BMS), Domain Therapeutics, Gilead, Roche, Medscape, MSD and AZ/Daiichi and received institutional research support from AstraZeneca/Daiichi, BMS and Roche outside the submitted work. RS reports non-financial support from Merck and BMS, research support from Merck, Puma Biotechnology and Roche, and personal fees from Roche, BMS and Exact Sciences for advisory boards. IRK received research grants from Novartis and Gilead. RHTK is an advisory board member for Amgen, AstraZeneca, Bayer, BMS, MSD, Novartis, Pfizer, Pierre Fabre Sante, Sanofi and Servier. All other authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Next generation sequencing of cell-free DNA (cfDNA) is a promising method for treatment monitoring and therapy selection in metastatic breast cancer (MBC). However, distinguishing tumor-specific variants from sequencing artefacts and germline variation with low false discovery rate is challenging when using large targeted sequencing panels covering many tumor suppressor genes. To address this, we built a machine learning model to remove false positive variant calls and augmented it with additional filters to ensure selection of tumor-derived variants. We used cfDNA of 70 MBC patients profiled with both the small targeted Oncomine breast panel (Thermofisher) and the much larger Qiaseq Human Breast Cancer Panel (Qiagen). The model was trained on the panels' common regions using Oncomine hotspot mutations as ground truth. Applied to Qiaseq data, it achieved 35% sensitivity and 36% precision, outperforming basic filtering. For 20 patients we used germline DNA to filter for somatic variants and obtained 245 variants in total, while our model found seven variants, of which six were also detected using the germline strategy. In ten tumor-free individuals, our method detected in total one (potentially germline) variant, in contrast to 521 variants detected without our model. These results indicate that our model largely detects somatic variants., (© 2023. The Author(s).)

Aim: Patients with HER2-positive (HER2+) metastatic breast cancer (mBC) develop brain metastases (BM) in up to 30% of cases. Treatment of patients with BM can consist of local treatment (surgery and/or radiotherapy) and/or systemic treatment. We undertook a systematic review and meta-analysis to determine the effect of different systemic therapies in patients with HER2+ mBC and BM., Methods: A systematic search was performed in the databases PubMed, Embase.com, Clarivate Analytics/Web of Science Core Collection and the Wiley/Cochrane Library. Eligible articles included prospective or retrospective studies reporting on the effect of systemic therapy on objective response rate (ORR) and/or median progression free survival (mPFS) in patients with HER2+ mBC and BM. The timeframe within the databases was from inception to 19 January 2022. Fixed-effects meta-analyses were used. Quality appraisal was performed using the ROBINS-I tool., Results: Fifty-one studies were included, involving 3118 patients. Most studies, which contained the largest patient numbers, but also often carried a moderate-serious risk of bias, investigated lapatinib and capecitabine (LC), trastuzumab-emtansine (T-DM1) or pyrotinib. The best quality data and/or highest ORR were described with tucatinib (combined with trastuzumab and capecitabine, TTC) and trastuzumab-deruxtecan (T-DXd). TTC demonstrated an ORR of 47.3% in patients with asymptomatic and/or active BM. T-DXd achieved a pooled ORR of 64% (95% CI 43-85%, I 2 0%) in a heavily pretreated population with asymptomatic BM (3 studies, n = 96)., Conclusions: Though our meta-analysis should be interpreted with caution due to the heterogeneity of included studies and a related serious risk of bias, this review provides a comprehensive overview of all currently available systemic treatment options. T-Dxd and TTC that appear to constitute the most effective systemic therapy in patients with HER2+ mBC and BM, while pyrotinib might be an option in Asian patients.

Purpose: To evaluate the feasibility and outcomes of a tailored, goal-directed, and exercise-based physical therapy program for patients with metastatic breast cancer (MBC)., Methods: This was an observational, uncontrolled feasibility study. The physical therapy intervention was highly tailored to the individual patient's goals, abilities, and preferences and could include functional, strength, aerobic, and relaxation exercises. Feasibility outcomes were participation rate (expected: 25%), safety, and adherence (percentage of attended sessions relative to scheduled sessions). Additional outcomes were goal attainment, self-reported physical functioning, fatigue, health-related quality of life, and patient and physical therapist satisfaction with the program., Results: Fifty-five patients (estimated participation rate: 34%) were enrolled. Three patients did not start the intervention due to early disease progression. An additional 22 patients discontinued the program prematurely, mainly due to disease progression. Median intervention adherence was 90% and no major intervention-related adverse events occurred. A goal attainment score was available for 42 patients (of whom 29 had completed the program and 13 had prematurely dropped out). Twenty-two (52%) of these patients achieved their main goal fully or largely and an additional 15 patients (36%) partially. Eighty-five percent would "definitely recommend" the program to other patients with MBC. We observed a modest improvement in patient satisfaction with physical activities (Cohen's d z 0.33)., Conclusion: The tailored intervention program was feasible in terms of uptake, safety, and outcomes and was highly valued by patients and physical therapists. However, disease progression interfered with the program, leading to substantial dropout., Trial Registration: NTR register: NTR6475.

No literature is available on the benign versus malignant breast lesion ratio in trans women (male sex assigned at birth, female gender identity). As hormone treatment in trans women results in breast tissue histologically comparable with cis (non-trans) women, breast pathology may be expected. Previously, an increased breast cancer risk compared with cis men have been observed. We aimed to investigate the frequency and outcomes of breast biopsies in trans women. Therefore, we retrospectively examined the medical files of 2616 trans women. To gain data on breast lesions, we linked our cohort to a national pathology database. In this study we found that 126 people (5%) had one or more breast biopsies (n = 139). Of these, 21 trans women had a breast biopsy before the start of hormone treatment, and 53 after the start of hormone treatment. Breast biopsies were performed predominantly because of abnormalities during physical examination (37%, n = 51/139 biopsies), or because of capsular formation or contraction (28%, n = 16/57 biopsies) in trans women with breast implants. The most common breast lesions after the start of hormone treatment were fibroadenomas (n = 20), breast cancer (n = 6), fibrosis (n = 5), cysts (n = 4), and infections (n = 4). The benign versus malignant breast biopsy ratio was 88:12, which is comparable to the ratio in cis women (90:10). This study shows breast lesions in a limited number of trans women. Since the indications and outcomes of biopsies in trans women were similar to those in cis women, it seems reasonable to follow breast care guidelines as developed for cis women., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This pilot trial explores the feasibility of measuring muscle contractile properties in patients with cancer, effects of exercise during chemotherapy on muscle contractile properties and the association between changes in contractile muscle properties and perceived fatigue., Method: Patients who received (neo)adjuvant chemotherapy for breast or colon cancer were randomized to a 9-12 week exercise intervention or a waitlist-control group. At baseline and follow-up, we measured knee extensor strength using maximal voluntary contraction (MVC), contractile muscle properties of the quadriceps muscle using electrical stimulation, and perceived fatigue using the Multidimensional Fatigue Inventory. Feasibility was assessed by the proportion of patients who successfully completed measurements of contractile muscle properties. Exercise effects on muscle contractile properties were explored using linear regression analyses. Between-group differences >10% were considered potentially relevant. Pearson correlation (r p ) of changes in contractile muscle properties and changes in perceived fatigue was calculated., Results: Twenty two of 30 patients completed baseline and follow-up assessments. Measurements of contractile properties were feasible except for muscle fatigability. We found a potentially relevant between-group difference in the rate of force development favoring the intervention group (1192 N/s, 95% CI = -335; 2739). Change in rate of force development was negatively correlated with change in perceived general (r p  = -0.54, P = .04) and physical (r p  = -0.59, P = .02) fatigue., Conclusion: Chemotherapy induces a decrease in the rate of force development, which may reflect a larger loss in type II muscle fibers. This may be attenuated with (resistance) exercise. The increase in the rate of force development was related to a decrease in perceived fatigue., (© 2020 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Background: Psychological distress is highly prevalent among patients with metastatic colorectal cancer., Aims: To perform an economic evaluation of a combined screening and treatment program targeting psychological distress in patients with metastatic colorectal cancer in comparison with usual care., Design: Societal costs were collected alongside a cluster randomized controlled trial for 48 weeks. A total of 349 participants were included., Setting: Participants were recruited from oncology departments at 16 participating hospitals in the Netherlands., Methods: Outcome measures were the Hospital Anxiety and Depression Scale and quality-adjusted life-years. Missing data were imputed using multiple imputation. Uncertainty was estimated using bootstrapping. Cost-effectiveness planes and cost-effectiveness acceptability curves were estimated to show uncertainty surrounding the cost-effectiveness estimates. Sensitivity analyses were performed to check robustness of results., Results: Between treatment arms, no significant differences were found in Hospital Anxiety and Depression Scale score (mean difference: -0.058; 95% confidence interval: -0.13 to 0.011), quality-adjusted life-years (mean difference: 0.042; 95% confidence interval: -0.015 to 0.099), and societal costs (mean difference: -1152; 95% confidence interval: -5058 to 2214). Cost-effectiveness acceptability curves showed that the probability of cost-effectiveness was 0.64 and 0.74 at willingness-to-pay values of €0 and €10,000 per point improvement on the Hospital Anxiety and Depression Scale, respectively. The probability that the intervention was cost-effective compared to usual care for quality-adjusted life-years was 0.64 and 0.79 at willingness-to-pay values of €0 and €20,000 per quality-adjusted life-year, respectively., Conclusion: The intervention is dominant over usual care, primarily due to lower costs in the intervention group. However, there were no statistically significant differences in clinical effects and the uptake of the intervention was quite low. Therefore, widespread implementation cannot be recommended.

Importance: Trials of adjuvant high-dose chemotherapy (HDCT) have failed to show a survival benefit in unselected patients with breast cancer, but long-term follow-up is lacking., Objective: To determine 20-year efficacy and safety outcomes of a large trial of adjuvant HDCT vs conventional-dose chemotherapy (CDCT) for patients with stage III breast cancer., Design, Setting, and Participants: This secondary analysis used data from a randomized phase 3 multicenter clinical trial of 885 women younger than 56 years with breast cancer and 4 or more involved axillary lymph nodes conducted from August 1, 1993, to July 31, 1999. Additional follow-up data were collected between June 1, 2016, and December 31, 2017, from medical records, general practitioners, the Dutch national statistical office, and nationwide cancer registries. Analysis was performed on an intention-to-treat basis. Statistical analysis was performed from February 1, 2018, to October 14, 2019., Interventions: Participants were randomized 1:1 to receive 5 cycles of CDCT consisting of fluorouracil, 500 mg/m2, epirubicin, 90 mg/m2, and cyclophosphamide, 500 mg/m2, or HDCT in which the first 4 cycles were identical to CDCT and the fifth cycle was replaced by cyclophosphamide, 6000 mg/m2, thiotepa, 480 mg/m2, and carboplatin, 1600 mg/m2, followed by hematopoietic stem cell transplant., Main Outcomes and Measures: Main end points were overall survival and safety and cumulative incidence risk of a second malignant neoplasm or cardiovascular events., Results: Of the 885 women in the study (mean [SD] age, 44.5 [6.6] years), 442 were randomized to receive HDCT, and 443 were randomized to receive CDCT. With 20.4 years median follow-up (interquartile range, 19.2-22.0 years), the 20-year overall survival was 45.3% with HDCT and 41.5% with CDCT (hazard ratio, 0.89; 95% CI, 0.75-1.06). The absolute improvement in 20-year overall survival was 14.6% (hazard ratio, 0.72; 95% CI, 0.54-0.95) for patients with 10 or more invoved axillary lymph nodes and 15.4% (hazard ratio, 0.67; 95% CI, 0.42-1.05) for patients with triple-negative breast cancer. The cumulative incidence risk of a second malignant neoplasm at 20 years or major cardiovascular events was similar in both treatment groups (20-year cumulative incidence risk for second malignant neoplasm was 12.1% in the HDCT group vs 16.2% in the CDCT group, P = .10), although patients in the HDCT group more often had hypertension (21.7% vs 14.3%, P = .02), hypercholesterolemia (15.7% vs 10.6%, P = .04), and dysrhythmias (8.6% vs 4.6%, P = .005)., Conclusions and Relevance: High-dose chemotherapy provided no long-term survival benefit in unselected patients with stage III breast cancer but did provide improved overall survival in very high-risk patients (ie, with ≥10 involved axillary lymph nodes). High-dose chemotherapy did not affect long-term risk of a second malignant neoplasm or major cardiovascular events., Trial Registration: ClinicalTrials.gov Identifier: NCT03087409.

Objectives: We aimed to investigate accelerometer output corresponding to physical activity intensity cut-points based on percentage of peak oxygen consumption (%VO 2 peak) and Metabolic Equivalent of Task (MET) value in women treated for breast cancer., Design: Laboratory study., Methods: Fifty female patients shortly after completion of treatment for breast cancer were included. VO 2 peak was determined during a cardiopulmonary exercise test. Subsequently, patients performed ten activities with different intensities while wearing an accelerometer on the right hip and a mobile oxycon to assess oxygen consumption. We studied the relationship between energy expenditure (expressed as %VO 2 peak and MET-value) and accelerometer output (in counts per minute (cpm)) with linear regression analyses. We determined accelerometer output corresponding to physical activity intensity cut-points (40% and 60%VO 2 peak; 3 and 6 MET) using regression equations., Results: VO 2 peak was 22.4mL/kg/min (SD 5.2) and resting metabolic rate was 3.1mL/kg/min (SD 0.6). Accelerometer output corresponding to the cut-points for moderate (40% VO 2 peak) and vigorous intensity (60% VO 2 peak) were 1123 and 1911, respectively. The analyses based on MET-values resulted in accelerometer output of 1189cpm for the moderate (3 MET) and 2768 cpm for the vigorous intensity cut-point (6 MET)., Conclusions: Accelerometer outputs for moderate and vigorous intensity physical activity were lower than commonly used cut-points (i.e. 1952 and 5724 cpm), irrespective of the method used to express energy expenditure (%VO 2 peak versus MET-value). Thus, categorizing physical activity intensities based on general-population cut-points, may underestimate physical activity intensities for women treated for breast cancer., (Copyright © 2019 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Purpose: In this study we aimed (1) to identify the most prevalent physical symptoms and functional limitations that limit physical activity of patients with palliative treatment for metastatic breast cancer (MBC) and (2) to identify their preferences for exercise-based physical therapy programs, as a first step towards the development of physical therapist (PT)-guided exercise programs for patients with MBC., Methods: We performed a mixed-method study that comprised a cross-sectional survey and two focus group sessions among patients with MBC. Survey results were analyzed using descriptive statistics. The focus groups were audio-taped, transcribed verbatim, and analyzed independently by two researchers, using directed content analysis., Results: A total of 114 women (response rate 61%) completed the survey (mean age 63.5, SD 10.2). Eighty-six percent of the women reported at least some level of physical problems limiting their ability to be physically active, of whom 46% reported substantial problems. The most prevalent problems were fatigue, painful joints, painful muscles, and shortness of breath. Uptake of exercise appeared to be limited. Exercise preferences varied strongly. Fifty-three percent indicated a preference for some form of PT-supervision, and 34% for a prolonged period of time (> 8 weeks). Focus group results clarified that patients' preferences for supervision, by PTs with special qualifications in oncology, were related to feelings of insecurity about their ability to self-manage physical functioning., Conclusions: Patients with MBC experience a broad range of physical health problems that limit their ability to be physically active. While preferences vary strongly, patients with MBC would value the availability of high quality, PT-guided, tailored exercise programs.

Background: Combining cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors with endocrine therapy is an effective strategy to improve progression-free survival in hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. There is a lack of comparative data to help clinicians decide if CDK4/6 inhibitors can best be added to first- or second-line endocrine therapy. Improvement in median progression-free survival in first-line studies is larger than in second-line studies, but CDK4/6 inhibitors have not consistently shown to improve overall survival or quality of life. They do come with added toxicity and costs, and many patients have lasting disease remission on endocrine therapy alone. No subgroup has been identified to select patients who are most likely to benefit from the addition of CDK4/6 inhibition in any line of treatment. Altogether, these factors make that the optimal strategy for using CDK4/6 inhibitors in clinical practice is unknown., Methods: The SONIA study is an investigator-initiated, multicenter, randomized phase III study in patients with HR+/HER2-negative advanced breast cancer. Patients are randomly assigned to receive either strategy A (first-line treatment with a non-steroidal aromatase inhibitor combined with CDK4/6 inhibition, followed on progression by fulvestrant) or strategy B (first-line treatment with a non-steroidal aromatase inhibitor, followed on progression by fulvestrant combined with CDK4/6 inhibition). The primary objective is to test whether strategy A is more effective than strategy B. The primary endpoint is time from randomization to second objective progression (PFS2). Secondary endpoints include overall survival, safety, quality of life, and cost-effectiveness. Five-hundred seventy-four events yield 89% power to show that strategy A has statistically significant, clinically meaningful superior PFS2 (according to ESMO-MCBS) in a log-rank test at the two-sided 95% confidence level. Given an accrual period of 42 months and an additional 18 months follow-up, inclusion of 1050 evaluable patients is required., Discussion: This study design represents daily clinical practice, and the results will aid clinicians in deciding when adding CDK4/6 inhibitors to endocrine therapy will benefit their patients most. Additional biomarker analyses may help to optimize patient selection., Trial Registration: http://clinicaltrials.gov: NCT03425838 (8 February 2018). EudraCT-number: 2017-002334-23 (29 September 2017).

Background: Cancer survivors have to deal with symptoms related to cancer and its treatment. In Oncokompas, cancer survivors monitor their quality of life by completing patient reported outcome measures (PROMs), followed by personalized feedback, self-care advice, and supportive care options to stimulate patient activation. The aim of this study was to investigate feasibility and pretest-posttest differences of Oncokompas including a newly developed breast cancer (BC) module among BC survivors., Material and Methods: A pretest-posttest design was used. Feasibility was investigated by means of adoption, usage, and satisfaction rates. Several socio-demographic and clinical factors, and health-related quality of life (HRQOL) were explored that might be associated with patient satisfaction. Barriers and facilitators of Oncokompas feasibility were investigated by evaluating nurse consultation reports. Differences in patient activation (Patient Activation Measure) and patient-physician interaction (Perceived Efficacy in Patient-Physician Interactions) before and after Oncokompas use were investigated., Results: In total, 101 BC survivors participated. Oncokompas had an adoption rate of 75%, a usage rate of 75-84%, a mean satisfaction score of 6.9 (range 0-10) and a Net Promoter Score (NPS) of -36 (range -100-100) (N = 68). The BC module had a mean satisfaction score of 7.6. BC survivors who received surgery including chemotherapy and/or radiotherapy were significantly more satisfied with Oncokompas than BC survivors with surgery alone (p = .013). Six facilitators and 10 barriers of Oncokompas feasibility were identified. After using Oncokompas, BC survivors scored significantly higher on patient activation (p = .007; r = .24), but not on patient-physician interaction (p = .75)., Conclusion: Oncokompas including a BC module is considered feasible, but needs further optimization to increase user satisfaction. This study shows the value of tailoring eHealth applications for cancer survivors to their specific tumor type. Oncokompas including the BC module seems to improve patient activation among BC survivors.

Background: Identifying predictors of treatment toxicity and overall survival (OS) is important for selecting patients who will benefit from chemotherapy. In younger patients with cancer, muscle mass and radiodensity are associated with treatment toxicity and OS. In this study, we investigated whether muscle mass, radiodensity, and strength were associated with treatment toxicity and OS in patients with advanced cancer aged 60 years or older., Materials and Methods: Before starting palliative chemotherapy, muscle mass and radiodensity were assessed using computed tomography scans and muscle strength was assessed using a hydraulic hand grip dynamometer. Treatment toxicity was defined as any toxicity resulting in dose reduction and/or discontinuation of treatment. Multiple logistic and Cox regression analyses were performed to study potential associations of muscle mass, radiodensity, and strength with treatment toxicity and OS, respectively., Results: The participants were 103 patients, with a mean age of 70 years, with advanced colorectal, prostate, or breast cancer. Muscle parameters were not significantly associated with treatment toxicity. Higher muscle strength was associated with longer OS (hazard ratio 1.03; 95% confidence interval 1.00-1.05). Muscle mass and radiodensity were not significantly associated with OS., Conclusion: Higher muscle strength at the start of palliative chemotherapy is associated with significantly better OS in older patients with advanced cancer. None of the investigated muscle parameters were related to treatment toxicity. Future studies are needed to evaluate whether muscle strength can be used for treatment decisions in older patients with advanced cancer., Implications for Practice: This study in older patients with advanced cancer showed that adequate muscle strength is associated with longer overall survival. The results of this study imply that muscle strength might be helpful in estimating survival and therefore in identifying older patients who will benefit from anticancer treatment., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2017.)

Background: The aim of this study was to estimate the total economic and health related burden of breast cancer in the Netherlands., Methods: Data on incidence, prevalence, mortality and survival were extracted from the Dutch National Cancer Registry and were used to calculate the economic and health related burden of breast cancer for overall, DCIS (stage 0), early- (stage I), locally advanced- (stage II-III) and metastatic- (stage IV) breast cancer by age groups and by year (if applicable)., Results: The overall incidence of breast cancer increased from 103.4 up to 153.2 per 100,000 women between 1990 and 2014. The increase was driven by DCIS and early breast cancer as the incidence of locally advanced and metastatic breast cancer remained stable. Between 1990 and 2014, ten-year overall survival rates increased from 87% to 93% for early breast cancer, 41% to 62% for locally advanced- and from 6% to 9% for metastatic disease. Annually, breast cancer in the Netherlands is responsible for approximately 3100 deaths, 26,000 life years lost, 65,000 Disability Adjusted Life Years (DALYs) and an economic burden of €1.27 billion., Conclusions: This study provides a comprehensive assessment of the burden of breast cancer and subsequent trends over time in the Netherlands.

Purpose: Delivery of exercise interventions to patients with early-stage breast cancer undergoing chemotherapy requires complex clinical decisions. The purpose of this study was to develop a framework to support clinical decisions for tailoring exercise interventions to common comorbidities and cancer treatment-induced adverse effects., Method: Tailored exercise prescriptions were developed in four steps, following the i3-S strategy. All steps were based on current best available evidence, complemented with expert opinions. First, common comorbidities and treatment-induced adverse effects were identified. In the subsequent steps, contra-indications and restrictions for exercise were described, along with possible exercise adaptations. In the final step, the obtained information was synthesized into a framework., Results: Prevalent comorbidities were hypertension, heart disease, diabetes mellitus, (osteo)arthritis, chronic obstructive pulmonary disease, and obesity. Adverse effects included conditions induced by pretreatment (e.g., lymphedema as a result of surgery) or by chemotherapy (e.g., reduced blood cell counts). Adaptations to the recommended exercise program were related to exercise tolerance, safety, and hygiene. A framework was proposed to guide clinical decisions during the exercise intervention., Conclusion: Comorbidities and adverse effects of breast cancer treatment require exercise adaptations. The proposed framework provides guidance on tailored exercise prescriptions in patients with breast cancer undergoing chemotherapy. Implications for Rehabilitation Exercise is recommended for patients with breast cancer undergoing chemotherapy, but requires complex clinical decisions of the health professional. We identified the most important comorbidities and adverse effects of breast cancer treatment, and the resultant contra-indications and restrictions to exercise. We incorporated these findings into a clinical decision framework that provides suggestions for exercise adaptations in patients with breast cancer undergoing chemotherapy.

Cross-sex hormone treatment of transsexual people may be associated with the induction and growth stimulation of hormone-related malignancies. We report here five cases of breast cancer, three in female-to-male (FtoM) transsexual subjects and two in male-to-female (MtoF) transsexual subjects. In the general population the incidence of breast cancer increases with age and with duration of exposure to sex hormones. This pattern was not recognised in these five transsexual subjects. Tumours occurred at a relatively young age (respectively, 48, 41, 41, 52 and 46 years old) and mostly after a relatively short span of time of cross-sex hormone treatment (9, 9-10 but in one after 30 years). Occurrence of breast cancer was rare. As has been reported earlier, breast tumours may occur in residual mammary tissue after breast ablation in FtoM transsexual people. For adequate treatment and decisions on further cross-sex hormone treatment it is important to have information on the staging and histology of the breast tumour (type, grade and receptor status), with an upcoming role for the androgen receptor status, especially in FtoM transsexual subjects with breast cancer who receive testosterone administration. This information should be taken into account when considering further cross-sex hormone treatment., (© 2015 Blackwell Verlag GmbH.)

Background: Despite the extensive clinical experience, it is still under debate to what extent patients with metastatic breast cancer (MBC) benefit from multiple lines of chemotherapy beyond standard first or second line treatment. Selection of patients with MBC who will benefit from treatment is crucial to improve outcome and reduce unnecessary toxicity. In this retrospective study, systemic treatment outcome for patients with metastatic MBC is being evaluated. We evaluated to what extent the clinical benefit of prior chemotherapy can predict the success of a subsequent treatment line., Methods: Ninety-one patients treated with chemotherapy for MBC between January 2005 and January 2009 were included in this study. Clinical characteristics of patients, choices of chemotherapy and response at first evaluation of every treatment line was evaluated based on radiologic and clinical data., Results: Patients received multiple systemic cytotoxic and biological (combination) therapies. 30% of these patients received more than five consecutive systemic (combination) treatments. First line chemotherapy was mostly anthracycline-based, followed by taxanes, capecitabine and vinorelbine. The response rate (RR, complete response plus partial response according to RECIST 1.1) decreased from 20% (95% CI 11-28%) upon first line of treatment to 0% upon the fourth line. The clinical benefit rate (combining RR and stable disease) decreased from 85% (95% CI 78-93%) in the first to 54% (95% CI 26-67) upon the fourth line. 24% of the patients with clinical benefit at first evaluation did not receive a subsequent line of treatment when progressive disease occurred, while sixty-one percent of the patients with progressive disease at first evaluation of a treatment did not receive a subsequent line of chemotherapy. When applied, the efficacy of a subsequent line of treatment was similar for patients independent of previous treatment benefit., Conclusion: The clinical benefit at first evaluation from systemic treatment in MBC does not predict for subsequent treatment benefit in this retrospective analysis. The fact that 61% of patients did not receive subsequent treatment after previous treatment failure suggests that either clinical judgement is of critical value in selection of patients to prevent them from unnecessary toxicity or, alternatively indicates that based on the assumption that prior treatment failure predicts for lack of benefit undertreatment of patients occurs. Therefore, a more adequate clinical judgement tool or predictive biomarkers for response are urgently needed to improve treatment outcome., (Copyright © 2015. Published by Elsevier Ltd.)

Purpose: Delayed chemotherapy-induced nausea and vomiting (CINV) remains an important adverse effect of moderately emetogenic chemotherapy not containing anthracyclines and cyclophosphamide (non-AC MEC). In this review, we summarize current literature to update recommendations for delayed CINV prophylaxis after non-AC MEC., Methods: We conducted a systematic search in PubMed and conference proceedings from ASCO, ESMO, and MASCC. Included randomized controlled trials (RCTs) aimed to prospectively evaluate the efficacy of two or more antiemetic strategies in the prevention of delayed CINV after the administration of non-AC MEC. At least one of the following endpoints was used: complete response, complete control, no nausea, no vomiting, and/or no use of rescue medication., Results: Our search provided 247 publications. Nine met the predefined criteria. Included RCTs reported outcomes on palonosetron, aprepitant, casopitant, netupitant/palonosetron (NEPA), olanzapine, and megestrol acetate., Conclusions: Superiority of palonosetron over first-generation 5-HT3 receptor antagonists for the prevention of acute and delayed CINV after non-AC MEC has not been proven. The addition of an NK1 receptor antagonist to first-generation 5-HT3 receptor antagonists does not significantly improve the incidence of delayed CINV after non-AC MEC. The efficacy of a single-day regimen of dexamethasone with palonosetron is non-inferior to multiday dexamethasone. NEPA, olanzapine, and megestrol acetate show highly effective complete response (CR) rates.

Background/introduction: Psychological distress occurs frequently in patients with cancer. Psychological distress includes mild and severe forms of both anxious and depressive mood states. Literature indicates that effective management of psychological distress seems to require targeted selection of patients (T), followed by enhanced care (E), and the application of evidence based interventions. Besides, it is hypothesized that delivering care according to the stepped care (S) approach results in an affordable program. The aim of the current study is to evaluate the (cost)-effectiveness of the TES program compared to usual care in reducing psychological distress in patients with metastatic colorectal cancer (mCRC)., Methods: This study is designed as a cluster randomized trial with 2 treatment arms: TES program for screening and treatment of psychological distress versus usual care. Sixteen hospitals participate in this study, recruiting patients with mCRC. Outcomes are evaluated at the beginning of chemotherapy and after 3, 10, 24, and 48 weeks. Primary outcome is the difference in treatment effect over time in psychological distress, assessed with the Hospital Anxiety and Depression Scale. Secondary outcomes include quality of life, patient evaluation of care, recognition and management of psychological distress, and societal costs., Discussion: We created optimal conditions for an effective screening and treatment program for psychological distress in patients with mCRC. This involves targeted selection of patients, followed by enhanced and stepped care. Our approach will be thoroughly evaluated in this study. We expect that our results will contribute to the continuing debate on the (cost-) effectiveness of screening for and treatment of psychological distress in patients with cancer., Trial Registration: This trial is registered in the Netherlands Trial Register NTR4034.

Introduction: The number of older patients with cancer is increasing. Standard clinical evaluation of these patients may not be sufficient to determine individual treatment strategies and therefore Geriatric Assessment (GA) may be of clinical value. In this review, we summarize current literature that is available on GA in elderly patients with solid malignancies who receive chemotherapy. We focus on prediction of treatment toxicity, mortality and the role of GA in the decision-making process., Design: We conducted a systematic search in PubMed. Studied populations needed to fulfill the following criteria: 65 years or older, diagnosis of solid malignancy, treatment with chemotherapy, submission to GA, either designed to study prediction of treatment toxicity or mortality or to evaluate the role of GA in the decision-making process., Results: Our search provided 411 publications. Thirteen met the predefined criteria. These studies revealed: (i) up to 64% of elderly patients suffer from severe toxicity caused by polychemotherapy, (ii) Nutritional status, functionality and comorbidity are often associated with worse outcome, (iii) GA reveals (unknown) geriatric problems in more than 50% of elderly patients with cancer and (iv) 21%-53% of chemotherapy regimens are being modified based on GA., Conclusions: In geriatric oncology, an accurate predictive test to guide anticancer treatment in order to prevent serious toxicity is needed. The value of GA in predicting toxicity and mortality in older patients with cancer undergoing treatment with chemotherapy has not been proven. It may be valuable in revealing geriatric problems but current evidence for its usefulness to guide treatment decisions in this setting is limited. However, we are convinced that GAs should be carried out to optimize treatment strategies in elderly patients with cancer to improve treatment efficacy and minimize toxicity., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Response to anticancer therapy is believed to be directly related to the concentration of the anticancer drug in the tumor itself. Assessment of intra-tumor drug pharmacokinetics can be helpful to gain more insight into mechanisms involved in the (in)sensitivity of tumors to anticancer therapy. We explored the pharmacokinetics of 5-fluorouracil in both plasma and tumor tissue during a 5-day continuous infusion of 5-fluorouracil in patients with cancer. Sampling for measurement of 5-fluorouracil in tumor tissue was performed using microdialysis., Experimental Design: In seven patients with an accessible (sub)cutaneous tumor treated with a continuous 5-fluorouracil infusion, plasma and microdialysate samples from tumor and normal adipose tissue were collected over a period of 5 days., Results: For six patients, drug concentrations in both tumor tissue and plasma were available. Concentration-time curves of unbound 5-fluorouracil were lower in tumor tissue compared to the curves in plasma, but exposure ratios of tumor tissue versus plasma increased during the 5-day infusion period. The presence of circadian rhythmicity of 5-fluorouracil pharmacokinetics in the tumor itself was demonstrated as 5-fluorouracil concentrations in tumor extracellular fluid were higher during the night than during daytime., Conclusion: Microdialysis was successfully employed in patients with cancer during a continuous 5-day 5-fluorouracil infusion. Plasma and tumor pharmacokinetics of 5-fluorouracil differed substantially with increasing 5-fluorouracil concentrations in tumor over time, possibly resulting from a lowered interstitial fluid pressure by 5-fluorouracil itself. This microdialysis 5-fluorouracil model might be useful to monitor the effect of drug delivery modulating strategies in future studies.

Background: Omeprazole is one of the most prescribed medications worldwide and within the class of proton pump inhibitors, it is most frequently associated with drug interactions. In vitro studies have shown that omeprazole can alter the function of metabolic enzymes and transporters that are involved in the metabolism of irinotecan, such as uridine diphosphate glucuronosyltransferase subfamily 1A1 (UGT1A1), cytochrome P-450 enzymes subfamily 3A (CYP3A) and ATP-binding cassette drug-transporter G2 (ABCG2). In this open-label cross-over study we investigated the effects of omeprazole on the pharmacokinetics and toxicities of irinotecan., Methods: Fourteen patients were treated with single agent irinotecan (600mg i.v., 90min) followed 3weeks later by a second cycle with concurrent use of omeprazole 40mg once daily, which was started 2weeks prior to the second cycle. Plasma samples were obtained up to 55h after infusion and analysed for irinotecan and its metabolites 7-ethyl-10-hydroxycampothecin (SN-38), SN-38-glucuronide (SN-38G), 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin (NPC) and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC) by high-performance liquid chromatography (HPLC). Non-compartmental modelling was performed. Toxicities were monitored during both cycles. Paired statistical tests were performed with SPSS., Results: The exposure to irinotecan and its metabolites was not significantly different between both cycles. Neither were there significant differences in the absolute nadir and percentage decrease of WBC and ANC, nor on the incidence and severity of neutropenia, febrile neutropenia, diarrhoea, nausea and vomiting when irinotecan was combined with omeprazole., Conclusion: Omeprazole 40mg did not alter the pharmacokinetics and toxicities of irinotecan. This widely used drug can, therefore, be safely administered during a 3-weekly single agent irinotecan schedule., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Purpose: Statins have for long been considered to play a potential role in anticancer treatment based upon their ability to inhibit the mevalonate synthesis pathway. This randomised phase II trial compared the efficacy and safety of pravastatin added to epirubicin, cisplatin and capecitabine (ECC versus ECC+P) in patients with advanced gastric carcinoma., Methods: Patients were randomised to receive up to six cycles of 3-weekly ECC with or without pravastatin (40 mg, once daily from day 1 of the first cycle until day 21 of the last cycle). Primary end-point was progression-free rate at 6 months (PFR(6 months)). Secondary end-points were response rate (RR), progression-free survival (PFS), overall survival (OS) and safety. For early termination in case of futility, a two-stage design was applied (P(0) = 50%; P(1) = 70%; α = 0.05; β = 0.10)., Results: Thirty patients were enrolled. PFR(6 months) was 6/14 patients (42.8%) in the ECC+P arm, and 7/15 patients (46.7%) in the control arm, and therefore the study was terminated after the first stage. In the ECC and ECC+P arm, RR was 7/15 (46.7%) and 5/15 (33.3%), median PFS was 5 and 6 months and median OS was 6 and 8 months, respectively. Toxicity data showed no significant differences, although there was a trend towards more gastrointestinal side-effects such as diarrhoea and stomatitis in the ECC+P arm., Conclusion: In this randomised phase II trial the addition of pravastatin to ECC did not improve outcome in patients with advanced gastric cancer. Therefore, further testing of this combination in a randomised phase III trial cannot be recommended., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: JNJ-26483327 is an oral, potent, multi-targeted tyrosine kinase inhibitor, inhibiting kinases of epidermal growth factor receptor (EGFR)-1, -2 and -4, rearranged during transfection (RET) receptor, vascular endothelial growth factor receptor (VEGFR)-3 and Src family (Lyn, Fyn, Yes) at low nanomolar concentrations. This phase I, accelerated titration study assessed maximum tolerated dose, safety, pharmacokinetics and pharmacodynamic effects of JNJ-26483327., Methods: Nineteen patients with advanced cancers received JNJ-26483327 continuous twice daily (BID) in escalating dose cohorts ranging from 100 to 2100 mg. Pharmacodynamic effects were assessed in paired skin biopsies and blood., Results: JNJ-26483327 was well tolerated in doses up to 1500 mg BID, with target-inhibition-related toxicity such as diarrhoea and skin rash, and other common reported toxicities being nausea, vomiting, anorexia and fatigue. At 2100 mg, two episodes of dose-limiting toxicity were observed, consisting of grade 3 anorexia and a combination of grade 3 anorexia and fatigue, respectively. Pharmacokinetics were dose proportional up to 1500 mg in which plasma levels were obtained showing anti-tumour activity in xenograft mouse models. Pharmacodynamic analysis did not show a substantial effect on expression of Ki-67, p27(kip1), phosphorylated mitogen-activated protein kinase, phosphorylated Akt and EGFR, and serum levels of sVEGFR-2, VEGF-C and VEGF-D remained unchanged. Stable disease was noted in six patients (32%)., Conclusion: JNJ-26483327 is well tolerated and shows a predictable pharmacokinetic profile; the recommended dose for further studies is 1500 mg BID.

The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin-pathway (PI3K/AKT/mTOR-pathway) plays a role in the regulation of cell proliferation, cell survival, angiogenesis and resistance to anti-tumor treatments. In many tumor types the PI3K/AKT/mTOR-pathway is found activated through several different underlying mechanisms. Since this pathway is believed to largely drive the malignant behavior of several of these tumors, mTOR-inhibition is considered an attractive means to apply as anti-tumor treatment. Currently, four mTOR-inhibitors are explored for clinical use: rapamycin, temsirolimus (CCI-779), everolimus (RAD001) and deforolimus (AP23573). As monotherapy, mTOR-inhibitors yield interesting anti-tumor activity against various tumor types at the expense of relatively mild toxicities. This recently resulted in the registration of two mTOR-inhibitors for patients with metastatic renal cell carcinoma (RCC) while randomized studies in other tumors are currently in progress. Furthermore, mTOR-inhibitors are well-suited drugs to combine with other anti-tumor drugs as in preclinical models mTOR-inhibition overcomes chemoresistance. Consequently, mTOR-inhibitor-containing multidrug regimens are subject to clinical studies. As holds true for all anti-tumor therapies, identification of patients who are likely to respond to mTOR-inhibitor-containing therapies is of utmost importance to avoid over- or undertreatment. Preliminary results suggest that several factors reflecting activation of mTOR in tumors may be used for this purpose. This review addresses the mechanism of action and current clinical experience with mTOR-inhibitors as well as their role in overcoming resistance to conventional therapies. Additionally, potential predictors of outcome to mTOR-inhibition are discussed.

Purpose: The somatostatin analogue [DOTA0, Tyr3]octreotide (DOTATOC) has previously been labeled with low linear energy transfer (LET) beta-emitters, such as 177Lu or 90Y, for tumor therapy. In this study, DOTATOC labeled with the high-LET alpha-emitter, 213Bi, was evaluated., Experimental Design: The radiolabeling, stability, biodistribution, toxicity, safety, and therapeutic efficacy of 213Bi-DOTATOC (specific activity 7.4 MBq/microg) were investigated. Biodistribution studies to determine somatostatin receptor specificity were done in Lewis rats at 1 and 3 hours postinjection. Histopathology of various organs was used to evaluated toxicity and safety. Therapeutic efficacy of 4 to 22 MBq 213Bi-DOTATOC was determined in a rat pancreatic carcinoma model., Results: Radiolabeling of the 213Bi-DOTATOC was achieved with radiochemical purity >95% and an incorporation yield > or = 99.9%. Biodistribution data showed specific binding to somatostatin receptor-expressing tissues. Administration of free 213Bi, compared with 213Bi-DOTATOC, resulted in higher radioactivity accumulation at 3 hours postinjection in the kidneys [34.47 +/- 1.40% injected dose/g (ID/g) tissue versus 11.15 +/- 0.46%, P < 0.0001] and bone marrow (0.31 +/- 0.01% ID/g versus 0.06 +/- 0.02%, P < 0.0324). A significant decrease in tumor growth rate was observed in rats treated with >11 MBq of 213Bi-DOTATOC 10 days postinjection compared with controls (P < 0.025). Treatment with >20 MBq of 213Bi-DOTATOC showed significantly greater tumor reduction when compared with animals receiving <11 MBq (P < 0.02)., Conclusions: 213Bi-DOTATOC showed dose-related antitumor effects with minimal treatment-related organ toxicity. No acute or chronic hematologic toxicities were observed. Mild, acute nephrotoxicity was observed without evidence of chronic toxicity. 213Bi-DOTATOC is a promising therapeutic radiopharmaceutical for further evaluation.